Propargyl/methyl furanosides as potential glycosyl donors

Article abstract of DOI:10.1039/c1cc13134f

Transfuranosylations are not well studied though many similar studies exist for transpyranosylation; herein, we report that propargyl/methyl d-ribf- and d-lyxf- give only 1,2-trans glycosides whereas d-araf- and d-xylf- result in a mixture of 1,2-trans an

Full text of DOI:10.1039/c1cc13134f

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COMMUNICATION
Propargyl/methyl furanosides as potential glycosyl donorswz
Srinivasa Rao Vidadala,a Gaddamannugu Gayatri,b G. Narahari Sastry*b and
Srinivas Hotha*c
Received 27th May 2011, Accepted 5th July 2011
DOI: 10.1039/c1cc13134f
Transfuranosylations are not well studied though many similar
studies exist for transpyranosylation; herein, we report that
propargyl/methyl D-ribf- and D-lyxf- give only 1,2-trans glycosides
whereas D-araf- and D-xylf- result in a mixture of 1,2-trans and
1,2-cis glycosides; observed facts are rationalised by compu-
tational studies.
synthesis of transglycosylated products from 2-C nitromethyl-
containing methyl glycosides,7a glyco-amino acid building
blocks,7b glycopolymers7c and glycopolypeptides.7d The fore-
going discussion enticed us to probe the gold activation
procedure for furanosylations with an eventual goal to synthe-
size antigenic motifs of LAM and AG present in Mycobacterium
tuberculosis.5b Accordingly, D-ribf (1a), D-xylf (1b), D-araf (1c)
and D-lyxf (1d) were synthesized from the corresponding aldoses
by simple Fischer glycosidation8 as the key step followed by
per-O-benzylation. Initially, propargyl ribofuranoside 1a was
allowed to react with aglycon 2a in the presence of AuBr3 in
CH3CN at room temperature for more than 3 days to observe
formation of the transglycosylated disaccharide 3a in 40% yield
in 1,2-trans (b-) fashion only (Scheme 1). The overall yield could
be improved to 72% without compromising on the 1,2-trans
stereoselectivity by the addition of 8 mol% each of AuBr3 and
AgOTf.9 Encouraged by the observed 1,2-trans stereoselectivity,
xylf 1b was subjected to same reaction conditions with aglycon 2a
to observe the 5 : 1 diastereomeric mixture of the 1,2-trans
(b-) and 1,2-cis (a-) disaccharides 4a in 67% yield. Similar
experiments with araf derivative 1c gave again diastereomeric
mixture of 10 : 1 1,2-trans (a-) and 1,2-cis (b-) disaccharides 5a in
66% yield whereas D-lyxf derivative 1d resulted in 1,2-trans
(a-) isomer 6a only in 69% yield (Scheme 1).9
Complex carbohydrate components of glycoproteins and glyco-
lipids are undoubtedly shown to be powerful in a variety of
biochemical and physiological processes in animals, yeast, cell-
cell adhesion, cytolysis, fertilization and hormone action.1
Synthesis of complex oligosaccharides is still a formidable
task in spite of several elegant approaches and as a consequence
superior methods for glycosidation need to be discovered.2
Ironically, most of the pioneering efforts are dedicated to
methods for the synthesis of pyranosides either because of their
more frequent occurrence in nature than furanosides or due to
the complexity in synthesizing them.3 However, recent identi-
fication of oligofuranosides in many natural products alerted
synthetic chemists to develop novel furanosylation methods
which are mild, stereoselective and catalytic from easily available
starting monosaccharides.4 Glycosyl phosphatidyl inositol,5a,b
arabinogalactan (AG),5c lipoarabinomannan (LAM)5c and
helminothosporium toxins5d are some of the examples that contain
complex oligofuranosides with immense biological importance.5
From our laboratory, we identified propargyl and methyl
glycopyranosides as glycosyl donors by the use of gold(III)
halides.6a,b The methodology is unique as it requires only a
catalytic amount of gold(III) salts and is traceless (no side
product from the leaving group) with a large substrate scope.6
The ability of methyl glycosides to behave as glycosyl
donors was linked to the Lewis and Brønsted acidity of AuBr3
in the presence of aglycons. In addition, recently, the gold(III)
activation protocol has been found to be excellent for the
To better understand the reasons for the observed experi-
mental trends, molecular modelling calculations have been
performed. Initially conformational searches for the reactants,
in their ionic forms, and products were carried-out by employing
the OPLS_2005 force field, using the ConfGen module of the
Schrodinger program package.10 This was followed by quantum
chemical calculations on all the conformations generated, with
a Division of Organic Chemistry, National Chemical Laboratory,
Pune-411 008, India
b Molecular Modelling Group, Indian Institute of Chemical
Technology, Hyderabad 500 008, India.
E-mail: gnsastry@gmail.com; Tel: +91-40-27193016
c Department of Chemistry, Indian Institute of Science Education &
Research, Pune-411 021, India. E-mail: s.hotha@iiserpune.ac.in;
Fax: +91 20 2589 9790; Tel: +91 20 2590 8015
w This article is part of the ChemComm ‘Glycochemistry and glycobiology’
web themed issue.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc13134f
Scheme 1 Propargyl furanosides as glycosyl donors.
c
9906 Chem. Commun., 2011, 47, 9906–9908
This journal is The Royal Society of Chemistry 2011

Table 1 Furanosides as glycosyl donors
Glycosyl donor
R5OH
Product
Time, %Yield a : b ratio
ribf-Series
1a
1a
1a
1a
xylf-Series
2b
2c
2d
2e
3b
3c
3d
3e
12 h, 77, b only
16 h, 73, b only
48 h, 60, b only
24 h, 68, b only
1b
1b
2b
2c
2d
4b
4c
4d
12 h, 90, 0.2 : 1
18 h, 75, 0.4 : 1
24 h, 68, 0.5 : 1
1b
araf-Series
1c
1c
2b
2c
2d
5b
5c
5d
12 h, 86, 1 : 0.2
12 h, 72, 1 : 0.1
24 h, 65, 1 : 0.1
1c
lyxf-Series
Scheme 2 Propargyl furanosides as glycosyl donors.
1d
1d
1d
1d
2b
2c
2d
2e
6b
6c
6d
6e
12 h, 85, a only
12 h, 75, a only
24 h, 61, a only
24 h, 62, a only
semiempirical calculations were done using the Gaussian
program suite.11
To understand the generality of the observed facts, trans-
furanosylations of glycosyl donors 1a to 1d with other aglycons
were studied. Representative aglycons from aliphatic
(2b), alicyclic (2c), carbohydrate (2d) and nucleosidic (2e)
alcohols were considered (Scheme 2). Gratifyingly, D-ribf
and D-lyxf donors 1a and 1d resulted in transglycosides
3b–3e and 6b–6e respectively in good yields with 1,2-trans
diastereoselectivity (Table 1).9 Similarly, D-xylf and D-araf
donors 1b and 1c reacted well with aglycons 2b–2d resulting
in a diastereomeric mixture of 1,2-trans and 1,2-cis glycosides
4b–4d, 5b–5d (Table 1).9
the semi-empirical AM1 method. Various conformations of
the products generated, along with the relative energies obtained
at AM1 level, are illustrated in Table 1 in the supporting
informationz. This enabled us to systematically sample the
conformational space and take the most stable conformation
to be subjected to geometry optimizations with the more reliable
B3LYP method with the 6-31G(d) basis set. The relative
reaction energies at the B3LYP/6-31G(d) level of theory are
depicted in Fig. 1.
From Fig. 1, it can be observed that the difference in
the relative reaction energies of a and b isomers of D-ribf is
ꢀ10.3 kcal molꢀ1 which suggests that the b isomer is preferred
over the a isomer. In contrast to these results the difference in
the relative reaction energies of the a and b isomers of D-lyxf is
about 15.0 kcal molꢀ1 which in turn suggests the formation of
the a isomer over the b isomer. The differences in the relative
reaction energies of a and b isomers for D-araf and D-xylf
derivatives are 3.42 and ꢀ0.8 kcal molꢀ1, respectively, which
indicates that while the a isomer is more preferred in the case
of D-araf, the b isomer is preferred for D-xylf. However such
small differences in the reaction energies between the two
isomers suggest the feasibility of the formation of both the
products. Thus the computational results corroborate well
with the observed experimental trends. All the DFT and
Owing to the observation that the transfuranosylations
occur at room temperature, we anticipated that the chemo-
selective activation of propargyl containing aglycons could be
possible.6c Accordingly, D-ribf donor 1a was treated with
propargyl pyranoside 2f under the aforementioned conditions
to obtain propargyl disaccharide 3f due to the activation of the
propargyl group of the ribf only (Scheme 3).
In continuation, we also explored the utility of methyl
furanosides (7–10) as glycosyl donors and aglycons 2a–2c
under gold catalysis conditions.6b The initial reaction of
methyl furanosides (7–10) with aglycon 2a at room temperature
did not afford the desired transglycosylated products
(3a, 4a, 5a and 6a) and hence we resorted to optimizing the
reaction conditions. The optimum temperature was found to
be 65 1C with acetonitrile as the solvent. Here again, we
observed the same diastereoselectivities; for example, D-ribf
(7) and D-lyxf (10) donors afforded 3a, 6a with 1,2-trans
diastereoselectivity whereas D-xylf (8) and D-araf (9) resulted
in glycosides 4a and 5a as a mixture of diastereomers.9 Similar
results were noticed when methyl furanosides (7–10) were
reacted with other glycosyl acceptors 2b and 2c to furnish
glycosylated products 3b, 3c, 4b, 4c, 5b, 5c, 6b, 6c in good
yields (Table 2).9
Fig. 1 Optimized structures of the products along with the relative
reaction energies (in kcal molꢀ1) at B3LYP/6-31G(d) level.
Scheme 3 Chemoselective activation of propargyl furanosides in the
presence of propargyl pyranoside.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9906–9908 9907

Table 2 Methyl furanosides as glycosyl donorsa
3 For a summary of furanosylations: T. L. Lowary, in Glycoscience:
Chemistry and Biololgy, ed. B. Fraser-Reid, K. Tatsuta and
J. Thiem, Springer, Heilderberg, 2001, vol. 3, p. 1696.
Glycosyl donor
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Time, Yield, a : b ratio
2a
2b
2c
3a 24 h, 69%, 4a 24 h, 65%, 5a 24 h, 60%, 6a 24 h, 60%,
b only 0.2 : 1 1 : 0.1 a only
3b 12 h, 90%, 4b 12 h, 91%, 5b 12 h, 85%, 6b 12 h, 89%,
b only 0.2 : 1 1 : 0.2 a only
3c 16 h, 69%, 4c 18 h, 75%, 5c 12 h, 71%, 6c 12 h, 66%,
b only 0.4 : 1 1 : 0.1 a only
a
Reaction conditions: AuBr3, AgOTf, CH3CN, 65 1C.
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In conclusion, we found that propargyl/methyl furanosides
can undergo transglycosylation reaction under gold(III)
catalysed glycosylations conditions. We observed that D-ribf
and D-lyxf give 1,2-trans selectivity and D-xylf and D-araf
result in mixture of both 1,2-cis and 1,2-trans glycosides.
Computational studies carried out at the B3LYP/6-31G(d)
level corroborated well with experimental observations. The use
of gold catalysed glycosidations for the synthesis of antigenic
fragments of infectious microbes is currently under way.
SRV thanks the financial support from CSIR, New Delhi. SH
thanks Department of Science & Technology, New Delhi for
SwarnaJayanti Fellowship. We thank CSIR for financial support.
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9908 Chem. Commun., 2011, 47, 9906–9908
This journal is The Royal Society of Chemistry 2011